The long-term goal of this project is to develop better therapies for acute influenza virus-induced respiratory disease and asthma. Influenza virus (an NIAID Category C pathogen) causes infection that is major public health problem, resulting in about 40,000 deaths and more than 200,000 hospitalizations annually in the US, with a total cost of over $10 billion/year. The 2009 swine flu pandemic demonstrated that patients with asthma are at particularly high risk for developing severe influenza infection, associated with hospitalization and death. As the numbers reflect, current therapies for acute influenza-induced respiratory disease are not fully effective, in part because the host-influenza interactions resulting in, and mechanisms by which influenza infection causes, acute respiratory disease and asthma are not fully understood. In Specific Aim 1 we will examine a specific intervention that targets a novel innate lymphoid cell type in the lungs, called natural helper cells or nuocytes. We recently showed that natural helper cells are specifically activated during influenza infection and are required for influenza-induced asthma in mice. We will use a unique experimental model of influenza-induced airway inflammation and airway hyperreactivity (AHR) (a cardinal feature of asthma) that develops independently of Th2 cells and adaptive immunity, and which may reflect human influenza-induced respiratory disease and asthma. The response is initiated when influenza infects alveolar macrophages, leading to pyroptosis and release of IL-33, which then activates natural helper cells to produce IL-13, which in turn mediates acute AHR. We will demonstrate that by targeting natural helper cells with c-Kit kinase inhibitors (imatinib or masitinib), influenza-induced airway pathology can be abolished. Such therapy may be much more effective than high dose corticosteroids, commonly used in patients with influenza-induced asthma. In Specific Aim 2 we will further refine the approach of targeting natural helper cells during influenza infection, and examine the interaction of influenza with host cells resulting in the production of IL-33, IL-25, and TSLP. All three of these cytokines potently activate natural helper cells, inducing them to produce IL-13. These studies will define host-influenza interactions and the biology of natural helper cells in this complex innate pathway, described only one year ago. Understanding the many components of this pathway is critical to provide key insights into how c-Kit kinase inhibitors fit into this pathway to reduce natural helper cell activity and influenza-induced asthma. These studies will focus on developing a novel therapeutic for acute, influenza-induced respiratory disease and asthma, which are serious, common clinical problems. The proposed therapeutic will target a host cell type activated by influenza and required for its pathogenesis. Moreover, study of this therapy will extend our fundamental understanding of mucosal immune responses.